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What is the best therapeutic approach to methicillin-resistant Staphylococcus aureus pneumonia?

Peyrani, Paula; Ramirez, Julio

Current Opinion in Infectious Diseases: April 2015 - Volume 28 - Issue 2 - p 164–170
doi: 10.1097/QCO.0000000000000149
RESPIRATORY INFECTIONS: Edited by Michael S. Niederman
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Purpose of review The purpose of this review is to define what the best therapeutic approach is for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) pneumonia.

Recent findings Although two meta-analyses reported conflicting findings, recent retrospective studies reported higher success rates in patients with MRSA pneumonia treated with linezolid when compared to vancomycin. Only registration trials are available for some anti-MRSA antibiotics, such as telavancin, ceftaroline, and ceftobiprole. Scarce information is available regarding the best therapeutic approach for MRSA community-acquired pneumonia.

Summary Linezolid seems to be a better choice than vancomycin for the treatment of MRSA ventilator-associated pneumonia. It is still unclear whether this affirmation holds for other forms of MRSA pneumonia. Further research is needed to define whether newer antibiotics are better alternatives than currently recommended agents.

Division of Infectious Diseases, University of Louisville, Louisville, Kentucky, USA

Correspondence to Paula Peyrani, Division of Infectious Diseases, University of Louisville, 501 E Broadway, Suite 140 – Louisville, KY 40202, USA. Tel: +1 502 852 3905; e-mail: p0peyr01@louisville.edu

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INTRODUCTION

Pneumonia remains an important cause of morbidity and mortality worldwide. Along with influenza, they constitute the eighth leading cause of death in the United States [1]. Appropriate initial antibiotic therapy is critical in order to achieve good outcomes. If empiric antibiotics do not cover the etiologic agent(s), adjusting therapy once the cause is known does not improve clinical outcomes [2,3].

Methicillin-resistant Staphylococcus aureus (MRSA) is a pathogen that can be the etiologic agent of pneumonia occurring in any setting. Although several antibiotics are available for the treatment of infections due to MRSA, just a few have been approved so far for the treatment of pneumonia. Vancomycin has been the standard of care for over 50 years but the difficulty in reaching appropriate serum levels and more recent data reporting worse outcomes with higher MRSA minimum inhibitory concentrations (MICs) has pushed the search for other options [4]. Linezolid, telavancin, ceftaroline, and ceftobiprole are antibiotics available in the market for the treatment of MRSA pneumonia. Tedizolid, dalbavancin, and oritavancin are currently being evaluated for the treatment of other infections apart from skin and soft tissue structures infection.

For the management of healthcare-associated pneumonia (HCAP), hospital-acquired pneumonia (HAP), and ventilator-associated pneumonia (VAP), the American Thoracic Society (ATS) and the Infectious Disease Society of America (IDSA) guidelines recommended either vancomycin or linezolid for the coverage of MRSA [3]. These guidelines mentioned, however, that, although further investigation was needed, linezolid could be a better choice for MRSA VAP under certain circumstances. During the last 2 years, a few more articles were published comparing vancomycin and linezolid with conflicting results [5▪–8▪]. Newer antibiotics have also been evaluated with scarcer information regarding the best therapeutic option to treat pneumonia due to MRSA [9–16].

Much less has been published in the area of community-acquired pneumonia (CAP) due to MRSA, in part related to the low prevalence of MRSA as the etiologic agent of CAP (approximately 2%) [17,18]. Nevertheless, community-associated MRSA seems to produce more severe pneumonia with increased mortality when compare to its hospital-acquired counterpart or even other organisms, and thus empiric coverage becomes critical.

Despite published data and years of experience using some of these antibiotics, it is still not clear what the best therapeutic approach is for the treatment of pneumonia due to MRSA.

In this article, the authors will discuss the following points:

  1. Characteristics of antibiotics with activity against MRSA.
  2. Recent evidence (within the last 12–18 months) for therapeutic approaches to treat MRSA pneumonia, focusing particularly on VAP and, to a lesser degree, on CAP.
  3. Best therapeutic approach for the treatment of MRSA VAP.
  4. Best therapeutic approach for the treatment of MRSA CAP.
Box 1

Box 1

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CHARACTERISTICS OF ANTIBIOTICS WITH ACTIVITY AGAINST METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS

The antibiotics with activity against MRSA are listed in Table 1[19].

Table 1

Table 1

Table 1

Table 1

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RECENT EVIDENCE FOR THERAPEUTIC APPROACHES

The two antimicrobials more extensively evaluated for the treatment of MRSA pneumonia have been linezolid and vancomycin. For all other anti-MRSA antibiotics, only registration trials and/or case series and small cohort studies have been published.

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Linezolid versus glycopeptides (vancomycin and teicoplanin)

Two meta-analyses and two retrospective cohort studies have been published over the last 2 years comparing these antibiotics, providing conflicting information [5▪–8▪]. Kalil et al.[5▪] evaluated the efficacy and safety of linezolid and vancomycin for the treatment of HAP. Nine randomized, clinical trials were included in this meta-analysis. Patients with HAP and VAP due to Gram-positive organisms were evaluated. There were not statistically significant differences in outcomes between the two groups. The adjusted absolute clinical response difference was 0.9% [95% confidence interval (CI) −1.2 to 3.1%]. The adjusted absolute mortality risk difference was 0.01% (95% CI −2.1 to 2.1%). Only three out of the nine trials reported information on ventilation before enrollment and one of these solely included patients with VAP [20]. Jiang et al.[7▪] analyzed 12 randomized clinical trials in a meta-analysis comparing linezolid versus vancomycin or teicoplanin. No statistically significant differences were found between the two groups regarding clinical cure (RR = 1.08, 95% CI 1.00–1.17) and mortality rates (RR = 0.95, 95% CI 0.83–1.09). Again, most of the trials enrolled participants with Gram-positive infections, including pneumonia.

More recently, Caffrey et al.[6▪] published a retrospective, cohort study in which 5271 patients with MRSA pneumonia treated with linezolid or vancomycin were evaluated. Significantly higher success rates were reported among those patients who received linezolid [adjusted heart rate (HR) 1.25, 95% CI 1.07–1.47]. No differences in mortality were found (adjusted HR 0.91, 95% CI 0.70–1.17). Peyrani et al.[8▪] evaluated exclusively patients with MRSA VAP. The result of this retrospective, cohort study reported that patients with MRSA VAP treated with linezolid had significantly higher clinical success rates when compared to those treated with vancomycin (RR, 1.24; 95% CI 1.06–1.32). As in all previously discussed studies, no significant difference in mortality rates were found between the two groups.

Although prior data have shown differences in the safety profile between linezolid and vancomycin, recent studies were not able to demonstrate these differences in regards to anemia, thrombocytopenia, and nephrotoxicity [5▪,7▪,8▪]. Authors agree that despite differences in definitions, the shorter antibiotic course utilized in the treatment of VAP may be the explanation.

No clinical trials have been performed in patients with MRSA CAP. Current recommendations of using vancomycin or linezolid are based on data provided by trials performed in patients with nosocomial pneumonia [18].

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Telavancin versus vancomycin

There were only two randomized, clinical trials published evaluating the efficacy and safety of telavancin for the treatment of MRSA HAP [21]. Telavancin showed to be noninferior to vancomycin. However, a trend in increased mortality was reported in patients with preexisting kidney insufficiency (creatinine clearance ≤50 ml/min). A few articles reviewing those two trials have been published over the last 2 years, re-emphasizing the concept that telavancin remains an alternative agent for the treatment of MRSA nosocomial pneumonia [13–15,22].

Telavancin has not been evaluated for the treatment of CAP.

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Ceftaroline

There are currently no randomized, clinical trials evaluating the efficacy of ceftaroline for the treatment of MRSA pneumonia. Pasquale et al.[11] published a case series of 10 patients with MRSA pneumonia including three patients with HAP and one with VAP. All patients with nosocomial pneumonia received prior anti-MRSA therapy and improved after receiving ceftaroline, suggesting that this antibiotic could be an alternative agent to treat this infection. Two retrospective cohort studies reported survival rates of approximately 90%.

None of these two studies documented the number of patients with VAP [9,10].

The two registration studies designed to evaluate the efficacy of ceftaroline for the treatment of CAP, excluded patients admitted to the ICU and those with suspected or confirmed MRSA infection. The Clinical Assessment Program and Teflaro Utilization Registry (CAPTURE) has been designed to evaluate the current use of ceftaroline in the United States. Recently published articles reviewing data from this registry reported clinical success between 75 and 80% in patients with CAP, including MRSA, treated with ceftaroline [23,24].

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Ceftobiprole

This is the first cephalosporin monotherapy approved in Europe for the treatment of CAP and HAP (excluding VAP). However, approval in the United States is still pending. A phase III, randomized, double-blind, clinical trial of patients with HAP reported noninferior overall clinical cure rates of ceftobripole when compared with ceftazidime along with linezolid (difference −2.9, 95% CI −10.0 to 4.1). This noninferiority was not sustained when patients with VAP were analyzed (ITT, 95% CI −26.0 to −1.5) [12,25]. MRSA was isolated in approximately 11% of enrolled participants. Furthermore, MRSA was only documented in 13 and 15% of the patients with VAP treated with ceftobiprole and ceftazidime/linezolid, respectively. The trial evaluating ceftobiprole for the treatment of CAP allowed the addition of linezolid to the ceftriaxone arm if MRSA was suspected [26]. Although ceftobiprole was noninferior to ceftriaxone ± linezolid, no conclusions can be made regarding MRSA CAP because only one patient with documented MRSA CAP was enrolled.

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Clindamycin

Scarce data are available regarding the efficacy of clindamycin for the treatment of MRSA pneumonia and it has been studied primarily in combination. A recently published case series of three patients admitted with necrotizing pneumonia due to Panton–Valentine leukocidin (PVL)-producing Staphylococcus aureus (2/3 were MRSA) reported successful outcomes using combination therapy that includes antibiotics capable of blocking toxin production such as clindamycin [27]. The authors pointed out that effective treatment should not only be targeted to the eradication of the organisms but also to blocking the effects of the toxin.

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Rifampin

The combination of vancomycin and rifampin has been recently analyzed in a review article [16]. One of the five trials included patients with MRSA pneumonia, whereas the other four were bacteremia/endocarditis trials. The authors concluded that there is limited evidence supporting the use of this combination and other alternative antibiotics should be considered instead of utilizing vancomycin along with rifampin.

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BEST APPROACH FOR THE TREATMENT OF METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS VENTILATOR-ASSOCIATED PNEUMONIA

Although several studies have been performed attempting to define the best treatment of MRSA nosocomial pneumonia, controversy still exists and no one single antibiotic is pointed out as the optimal choice. Vancomycin and linezolid are the available options that have been studied in more depth. The other remaining alternatives for treatment have been only evaluated in noninferiority clinical trials or in small case series and cohorts without a comparator arm.

It seems clear after all these years that mortality is not impacted by the antibiotic choice, which may not be that surprising considering that VAP attributable mortality seems to be low. Recently published data reported the overall rate to be 13%, with higher numbers in surgical patients and those with mid-range disease severity upon admission [28]. The authors conclude that attributable mortality is mainly related to longer stay in the ICU.

Clinical cure appears to be more uncertain. Almost all published studies to date have not found statistically significant differences in cure rates/clinical success when comparing linezolid with vancomycin (or teicoplanin). It is worth noting that most of the clinical trials enrolled participants with nosocomial pneumonia, some due to Gram-positive organisms in general and some others due to MRSA in particular. Although the number of patients with proven MRSA pneumonia is documented in the results, more vague information is available regarding the number of patient who developed HAP versus VAP and even if noted, these two groups were not differentiated when reporting clinical success rates. There were only two studies designed to enroll patients with MRSA VAP, and interestingly higher success rates for patients with MRSA VAP treated with linezolid were reported [8▪,20].

So what is the best therapeutic approach for MRSA VAP? It is the authors’ consideration that linezolid is a better choice for the treatment of MRSA VAP based on the following observations:

  1. Linezolid has better lung penetration.
  2. Documented higher failure rates with increased MICs for vancomycin still within the susceptible range.
  3. Difficulty of reaching recommended vancomycin trough levels within the critical time of the first 48 h of therapy.

No recommendations can be made at this time regarding the other anti-MRSA antibiotics given that there is scarce evidence comparing them with current treatment standards.

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BEST APPROACH FOR THE TREATMENT OF METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS COMMUNITY-ACQUIRED PNEUMONIA

Different from nosocomial pneumonia, MRSA empiric coverage in patients presenting with CAP is not a standard recommendation. However, community-associated MRSA CAP tends to be more severe and have higher mortality than CAP due to other organisms. Hence, the question here is not only what the best treatment is but also when it should be started.

A high index of suspicion may be needed in determining which patients should receive anti-MRSA coverage. Risk factors including but not limited to cavitation or necrotizing pneumonia seen on chest imaging, gross hemoptysis, neutropenia, and prior history of MRSA infections may guide the decision. However, being previously healthy is also considered to be a risk factor for MRSA CAP.

Data from clinical trials comparing antibiotic regimens for the treatment of MRSA CAP are not available. Most evidence originates from animal studies and nosocomial pneumonia literature. Considering that tissue damage is produced at least in part by the PVL toxin associated with community-associated MRSA, it can be expected that those antibiotics that block toxin production such as linezolid and clindamycin will have better results when compared to those that do not. So what is the best therapeutic approach for MRSA VAP? It is the authors’ consideration that a similar outcome can be reached using linezolid monotherapy or a combination of vancomycin along with clindamycin.

No recommendations can be made at this time regarding the other anti-MRSA antibiotics for CAP given that there is scarce evidence comparing them with current treatment standards.

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CONCLUSION

Based on existing literature, linezolid seems to be a better choice than vancomycin for the treatment of MRSA VAP. For other forms of MRSA pneumonia, the data are inconclusive regarding the choice of linezolid or vancomycin. Whether recently approved cephalosporins and other antibiotics being currently studied will prove to be even better choices remains still unclear.

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Acknowledgements

None.

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Financial support and sponsorship

None.

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Conflicts of interest

P.P. has received travel support from Pfizer, Inc. J.R. has received consultancy honoraria and research funding from Pfizer, Inc.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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REFERENCES

1. National Center for Health Statistics. National Vital Statistics Report. Deaths: Final Data for 2011. Available from: http://www.cdc.gov/nchs/data/nvsr/nvsr63/nvsr63_03.pdf. [Accessed 21 October 2014].
2. Frei CR, Attridge RT, Mortensen EM, et al. Guideline-concordant antibiotic use and survival among patients with community-acquired pneumonia admitted to the intensive care unit. Clin Therapeut 2010; 32:293–299.
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4. Holmes NE, Howden BP. What's new in the treatment of serious MRSA infection? Curr Opin Infect Dis 2014; 27:471–478.
5▪. Kalil AC, Klompas M, Haynatzki G, Rupp ME. Treatment of hospital-acquired pneumonia with linezolid or vancomycin: a systematic review and meta-analysis. BMJ Open 2013; 3:e003912.

Meta-analysis of nine clinical trials comparing vancomycin versus linezolid for the treatment of MRSA pneumonia reporting no statistically significant success rates between the two groups.

6▪. Caffrey AR, Morrill HJ, Puzniak LA, Laplante KL. Comparative effectiveness of linezolid and vancomycin among a national veterans affairs cohort with methicillin-resistant Staphylococcus aureus pneumonia. Pharmacotherapy 2014; 34:473–480.

Large retrospective, cohort study comparing vancomycin versus linezolid for the treatment of MRSA pneumonia. International Classification of Diseases 9 (ICD-9) codes were utilized to identify patients with MRSA pneumonia. Statistically significantly higher success rates were found in patients treated with linezolid.

7▪. Jiang H, Tang RN, Wang J. Linezolid versus vancomycin or teicoplanin for nosocomial pneumonia: meta-analysis of randomised controlled trials. Eur J Clin Microbiol Infect Dis 2013; 32:1121–1128.

Meta-analysis of 12 clinical trials comparing vancomycin or teicoplanin versus linezolid for the treatment of MRSA pneumonia reporting no statistically significant success rates between the two groups.

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Keywords:

antibiotic treatment; community-acquired pneumonia; hospital-acquired pneumonia; methicillin-resistant Staphylococcus aureus; pneumonia; ventilator-associated pneumonia

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